№ 2 (2003)

Выдающийся фармаколог XX века Василий Васильевич Закусов
(к 100-летию со дня рождения)

НЕЙРОФАРМАКОЛОГИЯ

АНТИПСИХОТИЧЕСКИЕ СРЕДСТВА: ОТ ФЕНОТИАЗИНОВ К АТИПИЧНЫМ НЕЙРОЛЕПТИКАМ НОВОГО ПОКОЛЕНИЯ

К. С. Раевский

The paper addresses evolution of the problem of creation, characterization of the pharmacological properties, and elucidation of the mechanisms of action of antipsychotic drugs (neuroleptics) – one of the most important classes of modern psychotropic drugs. The appearance of these drugs marked the onset of a new era in psychiatry, the era of psychoparmacology. Special attention is devoted to the investigations in this direction at the Institute of Pharmacology, which were headed by V. V. Zakusov.

СТРАТЕГИЯ СОЗДАНИЯ ДИПЕПТИДНЫХ НЕЙРОПСИХОТРОПНЫХ ЛЕКАРСТВЕННЫХ ПРЕПАРАТОВ

Т. А. Гудашева, А. П. Сколдинов

The paper considers a new strategy in the field of neuropsychotropic dipeptide drug design, the main points being as follows: (i) determination of the structural elements of dipeptides, such as fragments of amino acid side radicals and peptide bonds, in nonpeptide drugs; (ii) design of peptide analogs topologically close to the drug; (iii) synthesis and activity testing of these analogs; (iv) determination of the corresponding endogenous neuropeptide among the known neuropeptides or identification of the new neuropeptides in the brain of experimental animals. Using this approach, new pyroglutamyl- and prolyl-containing dipeptides were obtained based on the structure of the well-known classical nootropic drug piracetam. The new drugs exhibit nootropic activity in doses 100 – 10,000 times lower than those of piracetam. The structure of most active pyroglutamyl dipeptide pGlu-Asn-NH₂ coincides with that of the N-end fragment of the endogenous memory peptide AVP(4 – 9). Noopept (N-phenylacetylprolylglycine ethyl ester), patented in Russia and USA as a new nootropic drug, is currently under stage 2 of successful clinical trials. The main metabolite of noopept, cyclo-Pro-Gly, is identical to the endogenous dipeptide designed in this work and is most close analog of piracetam with respect to pharmacological activity. The universal character of the proposed strategy is demonstrated by the design of active dipeptide analogs of an atypical neuroleptic drug sulpiride. As a result, a potential dipeptide neuroleptic dilept was obtained, which has been patented in Russia and now passes broad preclinical trials.

СОЗДАНИЕ И ФАРМАКОЛОГИЯ НООТРОПНЫХ И АНТИДЕПРЕССИВНЫХ ПРЕПАРАТОВ НА ОСНОВЕ ЛИГАНДОВ ВАК-РЕЦЕПТОРОВ

В. И. Петров

The paper assesses the role of the system of exciting amino acids (EAA) in the interneuronal interactions in CNS. The results of basic investigations of the EAAergic system are summarized and the prospects for development of the related drugs possessing antidepressant activity are considered. Participation of the EAA system in pathogenesis of some neurologic and psychic diseases and in the pathologic alcohol addiction is analyzed. Taking into account that the psychic processes are realized by multitransmitter systems involving various brain structures, the possibility of using EAAergic drugs for controlling the balance between activating and inhibiting systems of brain is discussed. In this respect, special attention is given to EAAergic modulation of the monoaminergic and dopaminergic cerebral transmisison systems.

НЕЙРОХИМИЧЕСКИЙ АНАЛИЗ И ФАРМАКОЛОГИЧЕСКАЯ РЕГУЛЯЦИЯ КОРТИКОФУГАЛЬНЫХ МЕХАНИЗМОВ КОНТРОЛЯ НОЦИЦЕПТИВНЫХ СИГНАЛОВ В АФФЕРЕНТНЫХ ПУТЯХ

В. В. Чурюканов

Experimental and clinical data indicate that the cerebral cortex plays an important role in pain perception and endogenous antinociceptive system function. Moreover, the enhancement of descending inhibitory cortical control may be involved in the mechanisms of analgesic effect of some agents. The present study was designed to investigate the effect of cortical electrical stimulation (as a model of descending inhibitory control) on the behavioral and electrophysiological signs of nociceptive response, elucidate the mechanisms involved therein and evaluate the action of central analgesics (both opioid and non-opioid) on descending cortical control. In acute experiments on cats, the inhibitor y cortical influence upon neuronal activity produced by nociceptive stimuli (electrical stimulation of tooth pulp, C-fibers of afferent somatic nerves, afferent cardiac structures) was most marked after stimulation of the first and second sensory and fronto-orbital areas. In chronic experiments on rats, cortical stimulation reduced behavioral signs of visceral pain (writhing test) and also delayed the development of neuropathic pain syndrome along with lowering its intensity. m-Opioid receptor agonists (morphine, fentanyl) potentiated the inhibitory cortical effect on the evoked neuronal activity. Pentazocine, which has pronounced k-receptor agonist activity, was less effective. Naloxone eliminated the effects of both cortical stimulation and opioid analgesics. Serotonin receptor antagonist methysergide, as well as p-chlorophenylalanine significantly decreased inhibitory cortical control and the effect of opioids. Monoamine re-uptake inhibitors with analgesic properties (imipramine, fluoxetine) potentiated the inhibitory effect of cortical stimulation. Adreno-, dopamine-, acetylcholine-, GABA-receptor agents and antagonists of NMDA receptors had minor or no effect. Among non-narcotic analgesics, the cyclooxygenase inhibitors metamysole and ketorolak increased only moderately the descending cortical control of nociception. Thus, the cerebral cortex is able to control the nociceptive processing in different pain syndromes (somatic, visceral or neuropathic pain). Opioidergic and serotonergic systems play the key role in this control. Action through the cortical descending control is likely to be one of the components of the analgesic effect exerted by opioids and some other central analgesics.

ЭВОЛЮЦИЯ ПРОБЛЕМЫ НЕЙРОПРОТЕКЦИИ

Р. У. Островская

Although the modern concept of neuroprotection has been formulated quite recently, the basis of this approach was laid about four decades ago when Zakusov initiated the study of mechanisms involved in the neuroprotector action of GABA shunt metabolites (in particular, a-hydroxybutyric acid and succinic semialdehyde) during hypoxia. It was suggested to consider these agents as a system of endogenous neuroprotectors. The interest of Zakusov in endogenous regulators (including oligopeptides) had stimulated research in this direction and gave impact to the investigations of A. P. Skoldinov and T. A. Gudasheva initiated in the early 1980s. Proceeding from the original concept of the possibility of imitation of the action of neurotropic agents by their structural- conformational oligopeptide analogs, a number of biologically active stable dipeptides were obtained, based on pyroglutamate and proline, and high specific bioaccessibility of these dipeptides for the brain was established. Our investigations showed that these compounds not only possess nootropic activity (in a dose 1000 times lower than that of piracetam), but produce a pronounced neuroprotector action as well. Most thoroughly studied in this respect were substituted acyl-prolyl dipeptides, in particular, the drug noopept exhibiting a combined neuroprotector effect both in vitro and in vivo. Noopept decreases the extent of necrotic damage caused by photoinduced thrombosis of cortical blood vessels. It was established that the neuroprotector effect of noopept is related to its action upon the well-known “triad”, whereby the drug reduces neurotoxic effects of excess extracellular calcium, glutamate, and free radicals. Two additional components of the neuroprotector action of noopept are related to the antiinflammatory and antithrombotic activity. The prospects of using direct and indirect action upon neurotrophin system for neuroprotection purposes are considered. Taking into account common secondary mechanisms of the neuronal damage, it is possible to provide for pleotrophic brain protection with dipeptides in a broad spectrum of pathological states, including strokes, cerebral traumas, neurodegenerative processes, epilepsy, and schizophrenia.

СРАВНИТЕЛЬНАЯ ЭЛЕКТРОЭНЦЕФАЛОГРАФИЧЕСКАЯ ОЦЕНКА АНКСИОЛИТИКОВ АФОБАЗОЛА И ДИАЗЕПАМА НА ИНБРЕДНЫХ КРЫСАХ ЛИНИЙ MR И MNRA С РАЗНЫМ УРОВНЕМ ТРЕВОЖНОСТИ

С. Н. Кожечкин

The effects of two anxiolytic drugs, diazepam (10 mg/kg, i.p.) and afobazole (20 mg/kg, i.p.) on the EEG features was studied in MR and MNRA rats with different emotionality and anxiety levels in order to reveal an EEG marker of the anxiolytic action. For this purpose, 840 EEG parameters from 24 neocortex sites were determined and analyzed. In MR (but not in MNRA) rats, both diazepam and afobazole decreased the number of EEG parameters reliably changed upon the emotional-pain stress related to the intraperitoneal injections of 0,9% NaCl. Afobazole increased the theta-rhythm power in the spectral band of 4.75 – 7.25 Hz in MR rats, and in the band of 4.75 – 5.75 Hz in MNRA rats. Diazepam did not change the theta activity in MR rats, while decreasing it in the band of 6.00 – 7.25 Hz for MNRA rats. In addition, diazepam increased the spectral power in a broad frequency range of alpha and beta rhythms (8.75 – 17.25 Hz) in the rats of both lines, while afobazole did not produce such action. Common effects include a decrease in the spectral power within a narrow frequency band (7.5 – 8.5 Hz) at the boundary between theta and alpha regions. It is suggested that the latter effect can be used as the EEG marker of the anxiolytic action. The biopotential coherency in this frequency band was reduced in MR and MNRA rats only under the action of afobazole. The possibility of EEG changes related to the side action of anxiolytics and expediency of using the EEG markers in rats with different emotionality levels are discussed.

ВЛИЯНИЕ АНТИБИОТИКОВ-АМИНОГЛИКОЗИДОВ НА РАЗНЫЕ СТРУКТУРЫ СЛУХОВОГО АНАЛИЗАТОРА

В. П. Фисенко

Aminoglycoside antibiotics decrease the microphone potential amplitude and the auditory nerve potential in response to acoustic stimulation. These drugs suppress the bioelectrical activity of medulla, cerebral cortex, and olivo-cochlear efferent system. The experiments on freely moving cats showed that cortical response to electric stimulation of thalamocortical fibers originating from medial geniculate body are more sensitive to aminoglycoside antibiotics than the microphone potential and the auditory nerve potential.

ФАРМАКОЛОГИЯ СЕРДЕЧНО-СОСУДИСТОЙ СИСТЕМЫ

ФАРМАКОЛОГИЯ АНТИАРИТМИЧЕСКИХ СРЕДСТВ: НОВЫЕ АСПЕКТЫ

Н. В. Каверина, Г. Г. Чичканов

The paper describes new original drugs created at the Zakusov Institute of Pharmacology (Moscow). Cardiocyclide is a class III antiarrhythmic drug, producing a frequency-independent action; is a promising agent for the treatment of dangerous tachyarrhythmias. Bradizol is a class V antiarrhythmic drug producing a special bradycardiac action.

НЕЙРОПРОТЕКТОРНЫЕ И ЦЕРЕБРОВАСКУЛЯРНЫЕ ЭФФЕКТЫ ГАМК-МИМЕТИКОВ

Р. С. Мирзоян

The paper is devoted to the role of GABA system in the pharmacotherapy of ischemic brain injuries. In an analysis of the neuroprotector activity of GABA- mimetics, both their involvement in the maintenance of a balance between exciting and inhibiting processes and participation of the GABAergic mechanisms in regulation of the cerebrovascular tone are considered because proper blood supply is an important factor in the successful therapy of patients with ischemic brain injuries. Data available in the literature and the results of original investigations are summarized to assess the cerebrovascular and neuroprotector properties of GABA, as well as agonists and modulators of GABA receptors (muscimol, picamilon, phelbamate, clomethiazole, etc.). Particular attention is given to the neutroprotector and cerebrovascular activity of a new drug composition GABA-mimetic pirrolidone and pyroglutamic acid. This drug is capable of improving the cerebral blood supply, limiting the zone of ischemic injury, preventing an increase in the level of lactate and lipid peroxidation products, modifying nitric oxide content, and restoring the psychoneurological status of experimental animals with ischemic brain injury models.

ФАРМАКОГЕНЕТИКА

ГЕНЕТИКО-БИОХИМИЧЕСКОЕ РАЗВИТИЕ ПРОБЛЕМЫ ИНДИВИДУАЛЬНОЙ ЧУВСТВИТЕЛЬНОСТИ К ЛЕКАРСТВЕННЫМ СРЕДСТВАМ

Середенин С. Б., Вальдман Е. А.

The paper addresses evolution of the concept of individual sensitivity to drugs, based on the new pharmacogenetic and pharmacogenomic approaches. The possibility of geno- and phenotypy of the pharmacodynamic and pharmacokinetic processes, aimed at establishing the parameters ensuring reliable prediction of the individual response of a patient. The promising pharmacogenomic methods will allow to create preparations directly acting upon defective genes or the related products. Factors limiting the development of pharmacogenomic methods, related to the lack of data on the structure and physiological properties of protein products and their metabolites, are considered.

ФАРМАКОКИНЕТИКА

ГАРМОНИЗАЦИЯ ПРОВЕДЕНИЯ ИССЛЕДОВАНИЙ БИОЭКВИВАЛЕНТНОСТИ ЛЕКАРСТВЕННЫХ ПРЕПАРАТОВ: ВОПРОСЫ И ИХ ВОЗМОЖНОЕ РЕШЕНИЕ

В. П. Жердев, Г. Б. Колыванов, А. А. Литвин, А. К. Сариев

Problems encountered in the testing for bioequivalence of reproduced drugs (generics) are discussed in the parts incompletely resolved in domestic methodological recommendations. There are special cases when such drugs significantly vary in concentration and dosage, contain endogenous substances, exhibit intensive metabolism with a genetically polymorphous component, belong to “long-lived” compounds, and are intended for local administration. Also mentioned are problems related to insufficient sensitivity of analytical methods and some ethical aspects of investigations.

ДОСТАВКА ЛЕКАРСТВЕННЫХ ПРЕПАРАТОВ В МОЗГ С ПОМОЩЬЮ НАНОЧАСТИЦ

Р. Н. Аляутдин, Й. Кройтер, Д. А. Харкевич

Drugs can be delivered to brain with the aid of poly(butylcyanoacrylate) (PBCA) nanoparticles coated with polysorbate 80. These carriers can penetrate BBB and deliver drugs of various structures, including peptides, hydrophilic Compounds, and lipophilic compounds eliminated from brain with P-glycoprotein. When a suspension of polysorbate-coated PBCA nanoparticles is introduced into blood, apolipoproteins of the blood plasma adsorb on the particle surface and then interact with receptors of low-density lipoproteins situated in endothelial cells of cerebral vessels, thus stimulating endocytosis.

ИСТОРИЯ ФАРМАКОЛОГИИ

ЗНАЧЕНИЕ НАУЧНЫХ ИДЕЙ В. В. ЗАКУСОВА ДЛЯ СОВРЕМЕННОЙ ЭКСПЕРИМЕНТАЛЬНОЙ И КЛИНИЧЕСКОЙ ФАРМАКОЛОГИИ

Ю. Д. Игнатов

НЕЙРОХИМИЧЕСКАЯ ПРИРОДА ЛЕКАРСТВЕННОЙ ПСИХОСТИМУЛЯЦИИ: ВЗГЛЯД НА ПРОБЛЕМУ ЧЕТВЕРТЬ ВЕКА СПУСТЯ

Э. Б. Арушанян

Recent achievements in the molecular psychopharmacology led to a breakthrough in our understanding of the neurochemical mechanism of action of psy- chomotor stimulants. The specific activity of amphetamine-like compounds is probably related both to the modulation of monoaminergic transmission and to the conjugated mechanisms involving neuromediator amino acids, “early” genes, and a number of other factors.